http://chineseinput.net/에서 pinyin(병음)방식으로 중국어를 변환할 수 있습니다.
변환된 중국어를 복사하여 사용하시면 됩니다.
Loss-of-function mutations in SLC30A8 protect against type 2 diabetes
Flannick, Jason,Thorleifsson, Gudmar,Beer, Nicola L,Jacobs, Suzanne B R,Grarup, Niels,Burtt, Noë,l P,Mahajan, Anubha,Fuchsberger, Christian,Atzmon, Gil,Benediktsson, Rafn,Blangero, John,Bowden, Do Nature Pub. Co 2014 Nature genetics Vol.46 No.4
Loss-of-function mutations protective against human disease provide in vivo validation of therapeutic targets, but none have yet been described for type 2 diabetes (T2D). Through sequencing or genotyping of ∼150,000 individuals across 5 ancestry groups, we identified 12 rare protein-truncating variants in SLC30A8, which encodes an islet zinc transporter (ZnT8) and harbors a common variant (p.Trp325Arg) associated with T2D risk and glucose and proinsulin levels. Collectively, carriers of protein-truncating variants had 65% reduced T2D risk (P = 1.7 × 10<SUP>−6</SUP>), and non-diabetic Icelandic carriers of a frameshift variant (p.Lys34Serfs*50) demonstrated reduced glucose levels (−0.17 s.d., P = 4.6 × 10<SUP>−4</SUP>). The two most common protein-truncating variants (p.Arg138* and p.Lys34Serfs*50) individually associate with T2D protection and encode unstable ZnT8 proteins. Previous functional study of SLC30A8 suggested that reduced zinc transport increases T2D risk, and phenotypic heterogeneity was observed in mouse Slc30a8 knockouts. In contrast, loss-of-function mutations in humans provide strong evidence that SLC30A8 haploinsufficiency protects against T2D, suggesting ZnT8 inhibition as a therapeutic strategy in T2D prevention.
Yamauchi, Toshimasa,Hara, Kazuo,Maeda, Shiro,Yasuda, Kazuki,Takahashi, Atsushi,Horikoshi, Momoko,Nakamura, Masahiro,Fujita, Hayato,Grarup, Niels,Cauchi, Stephane,Ng, Daniel P K,Ma, Ronald C W,Tsunoda, Nature Publishing Group, a division of Macmillan P 2010 Nature genetics Vol.42 No.10
We conducted a genome-wide association study of type 2 diabetes (T2D) using 459,359 SNPs in a Japanese population with a three-stage study design (stage 1, 4,470 cases and 3,071 controls; stage 2, 2,886 cases and 3,087 controls; stage 3, 3,622 cases and 2,356 controls). We identified new associations in UBE2E2 on chromosome 3 and in C2CD4A-C2CD4B on chromosome 15 at genome-wide significant levels (rs7612463 in UBE2E2, combined P = 2.27 ? 10<SUP>??9</SUP>; rs7172432 in C2CD4A-C2CD4B, combined P = 3.66 ? 10<SUP>??9</SUP>). The association of these two loci with T2D was replicated in other east Asian populations. In the European populations, the C2CD4A-C2CD4B locus was significantly associated with T2D, and a combined analysis of all populations gave P = 8.78 ? 10<SUP>??14</SUP>, whereas the UBE2E2 locus did not show association to T2D. In conclusion, we identified two new loci at UBE2E2 and C2CD4A-C2CD4B associated with susceptibility to T2D.